Browsing by Subject "Chemotherapy resistance"

Now showing 1 - 5 of 5

Open Access
Epithelial-to-mesenchymal transition is not a major modulating factor in the cytotoxic response to natural products in cancer cell lines
(MDPI AG, 2021-09-27) Küçükkaraduman, Barş; Çiçek, Ekin Gökçe; Akbar, Muhammad Waqas; Demirkol Canlı, Seçil; Vural, Burçak; Gure, Ali Osmay
Numerous natural products exhibit antiproliferative activity against cancer cells by modulating various biological pathways. In this study, we investigated the potential use of eight natural compounds (apigenin, curcumin, epigallocatechin gallate, fisetin, forskolin, procyanidin B2, resveratrol, urolithin A) and two repurposed agents (fulvestrant and metformin) as chemotherapy enhancers and mesenchymal-to-epithelial (MET) inducers of cancer cells. Screening of these compounds in various colon, breast, and pancreatic cancer cell lines revealed anti-cancer activity for all compounds, with curcumin being the most effective among these in all cell lines. Although some of the natural products were able to induce MET in some cancer cell lines, the MET induction was not related to increased synergy with either 5-FU, irinotecan, gemcitabine, or gefitinib. When synergy was observed, for example with curcumin and irinotecan, this was unrelated to MET induction, as assessed by changes in E-cadherin and vimentin expression. Our results show that MET induction is compound and cell line specific, and that MET is not necessarily related to enhanced chemosensitivity.
Open Access
Identifying and targeting coding/non-coding molecular switches regulating drug resistance and metastasis in breast cancer
(2017-09) Raza, Umar
Breast cancer is the second most common cancer and the leading cause of cancer associated deaths in women worldwide. Despite the availability of large number and various types of therapy agents which are effective in limiting tumor burden at initial stages, cancer cells still manage to resist to therapy treatment and exhibit re-growth of existing tumor or metastasize to distant organs. Therefore, there is a dire need to identify underlying molecular mechanisms to enhance therapy response and to block metastasis. In addition to coding genome, non-coding RNAs have also play active role in controlling proliferation, apoptosis, invasion and drug resistance in cancer. Therefore, I aimed to identify novel coding/non-coding molecular switches regulating drug resistance and metastasis in breast cancer. In the first part of this dissertation, I identified miR-644a as a novel tumor suppressor inhibiting both cell survival and epithelial mesenchymal transition (EMT) whereby acting as pleiotropic therapy-sensitizer in breast cancer. Both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-terminal binding protein 1 (CTBP1) whose knock-outs by the CRISPR-Cas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, miR-644a/CTBP1-mediated upregulation of wild type- or mutant-p53 acts as a ‘molecular switch’ between G1-arrest and apoptosis by inducing p21 or Noxa, respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR- 644a or downregulation of CTBP1 was enough to shift the balance between cell cycle arrest and apoptosis in favor of apoptosis through the upregulation of Noxa. Notably, p53-mutant patients, but not p53-wild type ones, with high CTBP1 level have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, modulation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis. In the second part of this dissertation, I performed whole transcriptome sequencing with downstream pathway analysis in the chemoresistant triple negative breast cancer (TNBC) tumors we developed in vivo. This suggested a potential role of integrins and hypoxia in chemoresistance. Mechanistically, we showed that our candidate gene is hypoxia-induced and is overexpressed in resistant tumors, and activates integrin subunit alpha 5 (ITGA5). In the meantime, hypoxia-mediated downregulation of a miRNA targeting our candidate gene, leads to further activation of the ITGA5. This culminates in the activation of FAK/Src signaling thereby mediating resistance. Importantly, higher expression of our candidate gene, or lower expression of miRNA was associated with poorer relapse-free survival only in chemotherapy-treated TNBC patients. Finally, inhibition of candidate gene increased the efficacy of chemotherapy in highly aggressive TNBC models in vivo providing pre-clinical evidence for testing inhibitors against our candidate gene to overcome chemoresistance in TNBC patients.
Open Access
miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance
(Springer Verlag, 2016-06) Mutlu, M.; Raza, U.; Saatci, Ö.; Eyüpoğlu, E.; Yurdusev, E.; Şahin, Ö.
MicroRNAs (miRNAs) are 20–22-nucleotide small endogenous non-coding RNAs which regulate gene expression at post-transcriptional level. In the last two decades, identification of almost 2600 miRNAs in human and their potential to be modulated opened a new avenue to target almost all hallmarks of cancer. miRNAs have been classified as tumor suppressors or oncogenes depending on the phenotype they induce, the targets they modulate, and the tissue where they function. miR-200c, an illustrious tumor suppressor, is one of the highly studied miRNAs in terms of development, stemness, proliferation, epithelial-mesenchymal transition (EMT), therapy resistance, and metastasis. In this review, we first focus on the regulation of miR-200c expression and its role in regulating EMT in a ZEB1/E-cadherin axis-dependent and ZEB1/E-cadherin axis-independent manner. We then describe the role of miR-200c in therapy resistance in terms of multidrug resistance, chemoresistance, targeted therapy resistance, and radiotherapy resistance in various cancer types. We highlight the importance of miR-200c at the intersection of EMT and chemoresistance. Furthermore, we show how miR-200c coordinates several important signaling cascades such as TGF-β signaling, PI3K/Akt signaling, Notch signaling, VEGF signaling, and NF-κB signaling. Finally, we discuss miR-200c as a potential prognostic/diagnostic biomarker in several diseases, but mainly focusing on cancer and its potential application in future therapeutics.
Open Access
Multiomics approaches to overcome drug resistance in cancer
(2021-09) Küçükkaraduman, Barış
Chemotherapy resistance remains one of the major challenges in cancer treatment. Most of the studies on drug resistance have focused on genetic evolution of cancer cells; however, this focus has shifted to non-genetic and epigenetic mechanisms. There is accumulating evidence that mechanisms of drug resistance are not mutually exclusive but instead coexist within a given cancer to develop resistance and therapy failure. Hence, overcoming resistance requires the comprehension of these complex biological processes. Here, we aimed to characterize drug resistance mechanisms by performing both single omics interrogations and multi-omics integrative analysis. For this purpose, we conducted Gene Set Enrichment Analysis (GSEA), functional enrichment analysis on protein-protein interaction (PPI) networks and miRNA-target networks for interpreting gene and miRNA expression data. To gain further biological insights on resistance mechanisms, we focused on identifying a multi-omics molecular signature that discriminates cancer cells based on their drug response profiles. Collectively, these in silico analyses suggested the epithelial-to mesenchymal transition (EMT) as a mediator of 5-FU/irinotecan resistance in colon cancer and irinotecan/gemcitabine resistance in pancreatic cancer. Drug sensitive cancer cells exhibited a more epithelial phenotype with increased cell proliferation. Multi-omics integration analysis revealed some EMT-related genes such as TGM2 and FOSL1, to contribute differential drug response in cancer cells. On the other hand, response of breast cancer cells to doxorubicin exhibited an opposite profile in which mesenchymal phenotype is sensitive while resistant cells have epithelial phenotype. Secondly, we aimed to induce mesenchymal-to-epithelial transition to overcome EMT-mediated drug resistance. We selected eight natural compounds and two re-purposed agents that have been shown to reverse EMT in various studies. We noted transcriptional changes suggesting a shift towards a more epithelial phenotype in 4 out of the 6 cell lines upon treatment with at least one compound tested. None of the natural compounds or re-purposed agents triggered MET in all cancer cells screened. In addition, compounds with clear or slight MET induction did cause these effects in a specific cell line or only in specific cancer type. We investigated next whether the treatment with natural compounds would result in chemosensitization. MET induction by natural compounds is not uniformly related to increased sensitivity to chemotherapeutics but can result in occasional synergistic or additive effects. Lastly, based on cytotoxic activity of a novel c-Src inhibitor 10a in 15 melanoma cells, we report the identification of a new gene signature that can predict chemosensitivity to 10a. Two distinct phenotypes of cells, defined as sensitive and resistant, were further analyzed to reveal an underlying mechanism for this differential response to 10a. We found that proliferative or mesenchymal features of the cells are associated with distinct sensitivity of 10a. Through a protein−chemical interaction network analysis, we identified that three histone deacetylase inhibitors, valproic acid, entinostat, and trichostatin A, were predicted to synergize with 10a. The synergizing effect of valproic acid was validated in vitro. We also aimed to define a minimal number of genes that could be used as biomarkers of 10a sensitivity. We show that the expression level of four genes can be used to predict drug sensitivity against 10a.
Open Access
Targeting mirna-protein regulatory networks to enhance chemotherapy response in BRCA1-mutated TNBCs
(2016-09) Eyüpoğlu, Erol
Breast cancer is the second most common cancer and the leading cause of cancer associated deaths in women worldwide. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. BRCA1-mutated TNBC patients generally respond well to DNA cross-linking agents like Cisplatin. However, most of the patients acquire resistance and eventually die. Therefore, there is a dire need of developing promising approaches to enhance chemo-response, hence, extending the survival of TNBC patients. MicroRNAs (miRNAs) play active role in controlling proliferation, apoptosis, invasion and drug resistance in cancer. However, the role of miRNA-protein interactions as a regulatory network in determining chemotherapy response of TNBCs has not been elucidated yet. Thus, we aimed to delineate miRNAs and miRNA-protein regulatory networks controlling chemotherapy resistance/response in BRCA1–mutated TNBCs. We firstly confirmed that BRCA1-mutated breast cancer cells are more sensitive to Cisplatin as compared to BRCA1-competent cells. Afterwards, developing acquired chemotherapy resistant cell line model and using next generation sequencing technology (both miR-Seq and RNA-Seq), we have unravelled that p53 signalling is the upstream regulator of Cisplatin resistance. Moreover, with the use of Ingenuity Pathway Anlaysis (IPA) which uses omics data from a variety of experimental platforms, we analyzed, combined and modelled miRNA-mRNA interactions regulating Cisplatin resistance for the first time in a network manner. Interestingly, we identifed several network motifs e.g. coherent and incoherent feedforward loops centered around p53 protein which need further experimental validations. Again for the first time, this study has reported the re-sensitization effect of miR-455 family on Cisplatin resistance in breast cancer. Overall, findings of this study might be used as an alternative strategy for treatment of BRCA1-mutated TNBCs by modulating miRNAs and their targets to re-sensitize Cisplatin resistant tumors.